Chemistry of drugs

Chemistry of Drugs DAVID E NEWTON One Last Time for John McArdle, Lee Nolet, Richard Olson, David Parr, David Rowand, Jeff Williams, and John D’Emilio Thanks for the memories! ◆ Chemistry of Drugs Copyright © 2007 by David E Newton All rights reserved No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage or retrieval systems, without permission in writing from the publisher For information contact: Facts On File, Inc An imprint of Infobase Publishing 132 West 31st Street New York NY 10001 Library of Congress Cataloging-in-Publication Data Newton, David E Chemistry of drugs / David E Newton p cm—(The new chemistry) Includes bibliographical references and index ISBN-10: 0-8160-5276-X ISBN-13: 978-0-8160-5276-9 Pharmaceutical chemistry—Juvenile literature Drugs—Juvenile literature I Title RS403.N496 2007 615.'19—dc22 2006030004 Facts On File books are available at special discounts when purchased in bulk quantities for businesses, associations, institutions, or sales promotions Please call our Special Sales Department in New York at (212) 967-8800 or (800) 322-8755 You can find Facts On File on the World Wide Web at http://www.factsonfile.com Text design by James Scotto-Lavino Illustrations by George Barille /Accurate Art, Inc Project editing by Dorothy Cummings Printed in the United States of America MP FOF 10 This book is printed on acid-free paper ◆ CONTENTS Preface Introduction UNDERSTANDING THE WAY DRUGS WORK IN THE BODY Early Humans Discover Drugs Types of Drugs How Drugs Work: Disease Prevention How Drugs Work: Altering Mental Processes Otto Loewi (1873–1961) The Future of Drug Design and Development Candace Beebe Pert (1946– ) NATURAL PRODUCTS The Use of Natural Products as Drugs in History Natural Products and the Rise of Modern Chemistry Robert Burns Woodward (1917–1979) Microorganisms as the Source of Drugs Marine Organisms as a Source of Drugs Plant Products as the Source of New Drugs Monroe Wall (1916–2002) and Mansukhlal Wani (1925– ) The Search for New Natural Product Drugs Natural Product Research and Biodiversity Natural Products as Dietary Supplements The Safety of Natural Products as Drugs vii ix 1 10 15 17 18 20 21 23 26 28 30 33 36 38 40 41 47 RECOMBINANT DNA AS A NEW SOURCE OF DRUGS Principles of Recombinant DNA Paul Berg (1926– ) The Process of Recombinant DNA Werner Arber (1929– ) Drugs Produced by Recombinant DNA Pharming as a Source of Genetically Modified Drugs Pharming and Transgenic Technology Pros and Cons of Pharming DESIGNER DRUGS What Are Designer Drugs? Illegal Designer Drugs U.S Drug Enforcement Administration Fentanyl Analogs Phenylethylamine Analogs Methamphetamine MDMA Alexander “Sasha” Shulgin (1925– ) Meperidine Analogs Phencyclidine Analogs GHB and Rohypnol Guesses and Risks RATIONAL DRUG DESIGN: STRUCTURE-ACTIVITY RELATIONSHIPS AND COMBINATORIAL CHEMISTRY Steps in the Development of a New Drug Rational Drug Design Structure-Activity Relationships Elements of Structure-Activity Relationship Drug Design Modifications in Pharmcophores Quantitative Structure-Activity Relationships Louis Plack Hammett (1894–1987) Combinatorial Chemistry Solid-Phase Synthesis R Bruce Merrifield (1921–2006) 53 54 58 61 64 64 72 74 77 83 85 89 90 92 94 95 96 100 104 106 108 111 114 115 117 118 123 127 131 132 134 136 138 Solution-Phase Synthesis Applications of Combinatorial Chemistry 148 156 CONCLUSION 159 Glossary Further Reading Index 163 169 173 ◆ PREFACE T he subject matter covered in introductory chemistry classes at the middle and high school levels tends to be fairly traditional and relatively consistent from school to school Topics that are typically covered in such classes include atomic theory, chemical periodicity, ionic and covalent compounds, equation writing, stoichiometry, and solutions While these topics are essential for students planning to continue their studies in chemistry or the other sciences and teachers are correct in emphasizing their importance, they usually provide only a limited introduction to the rich and exciting character of research currently being conducted in the field of chemistry Many students not planning to continue their studies in chemistry or the other sciences may benefit from information about areas of chemistry with immediate impact on their daily lives or of general intellectual interest Indeed, science majors themselves may also benefit from the study of such subjects The New Chemistry is a set of six books intended to provide an overview of some areas of research not typically included in the beginning middle or high school curriculum in chemistry The six books in the set—Chemistry of Drugs, Chemistry of New Materials, Forensic Chemistry, Chemistry of the Environment, Food Chemistry, and Chemistry of Space—are designed to provide a broad, general introduction to some fields of chemistry that are less commonly mentioned in standard introductory chemistry courses They cover topics ranging from the most fundamental fields of chemistry, such as the origins of matter and of the universe, to those with important applications to everyday life, such as the composition of foods vii viii CHEMISTRY OF DRUGS and drugs The set title The New Chemistry has been selected to emphasize the extensive review of recent research and advances in each of the fields of chemistry covered in the set The books in The New Chemistry set are written for middle school and high school readers They assume some basic understanding of the principles of chemistry that are generally gained in an introductory middle or high school course in the subject Every book contains a large amount of material that should be accessible to the interested reader with no more than an introductory understanding of chemistry and a smaller amount of material that may require a more advanced understanding of the subject The six books that make up the set are independent of each other That is, readers may approach all of the books in any sequence whatsoever To assist the reader in extending his or her understanding of each subject, each book in the set includes a glossary and a list of additional reading sources from both print and Internet sources Short bibliographic sketches of important figures from each of the six fields are also included in the books ◆ INTRODUCTION T he search for chemicals that will provide relief from pain, cure disease and infection, and offer an escape from the real world has been a part of virtually every known human culture In the earliest period of human civilization, plants, animal products, and minerals were the major source from which such chemicals were obtained Many of those products—ranging from natural poisons obtained from frogs and certain types of plants to rocky minerals such as compounds of arsenic to mind-altering substances derived from mushrooms and cacti—are still used in at least some parts of the world as a means of capturing prey, for the treatment of disease, or for recreational purposes Indeed, many pharmaceutical chemists believe that the natural world contains an almost endless supply of yet-to-be-discovered chemicals that will significantly augment the world’s supply of drugs People’s dependence on the natural world for drugs began to change, however, at the beginning of the 18th century During this period, chemists became adept at designing and synthesizing synthetic chemicals with properties similar to or superior to those of natural medications Compounds originally developed for other purposes, such as dyeing, were found to have therapeutic value to humans and other animals In addition, chemists found that making relatively minor changes in the chemical structure of a substance resulted in the formation of new compounds that were often safer and/or more efficacious than the original compounds from which they were derived The lessons learned during these early decades ix x CHEMISTRY OF DRUGS of modern chemistry have continued to drive much of the drug development research that continues in the 21st century Chemists are also drawing on newer and more revolutionary techniques for the design and development of new drugs For example, the procedure known as recombinant DNA has been used to manufacture new drugs almost from the day it was imagined The fruits of that technique in drug development have been a bonanza for the world’s pharmaceutical companies and brought relief from pain and suffering for untold numbers of humans around the world Today, methods of drug development are drawing on chemical techniques essentially unknown only a few decades ago For example, some researchers think that new approaches, such as structure-activity relationship design and combinatorial chemistry, are likely to be the most powerful source of new drugs in the new century Research programs that once cost more than a billion dollars per drug candidate and lasted upwards of 10 years have now been “streamlined” by the use of these new techniques, providing the possibility of a cornucopia of new drug products for the world’s medical profession These developments have been accompanied by a corresponding explosion in the variety of chemical products available for recreational use As has always been the case, such products are in high demand by a relatively small proportion of the population who look for chemicals as a way of providing them with an “out-of-body” experience Almost without exception, however, those drugs hold the potential for producing enormous risks for one’s physical, mental, and emotional health Drug development and research today offer some of the most challenging and exciting research available to any chemist The fruits of that research have the potential for curing diseases, such as cancer, that have proved resistant to treatment by the medical sciences since the dawn of time Questions as to the cost of the research needed for such accomplishments and the risk of misuse of some drugs developed by it still remain to be answered Chemistry of Drugs provides an introduction to the most common processes by which chemists design and develop drugs today It describes the 166 CHEMISTRY OF DRUGS orthogonal library In combinatorial chemistry, a mechanism for carrying out the synthesis of many compounds at the same time by which the characteristic properties of one or more of those compounds can be identified Also known as an indexed library parallel synthesis See SOLUTION-PHASE SYNTHESIS Parkinson’s disease A degenerative disease of the nervous system characterized by tremor and impaired muscular coordination patient-directed designer drug A drug developed to meet the medical needs of very specific types of individuals pharmacopoeia A catalog of drugs, chemicals, and medicinal preparations pharmacogenomics The study of the way in which individuals respond to various drugs because of their unique genetic makeup pharmacophore The physical and chemical structure of some fundamental part of a molecule that binds to an enzyme, a cell receptor, or some other biological target to produce a biological effect pharming A modern field of technology in which traditional methods of farming are used for the production of pharmaceutical chemicals Also known as MOLECULAR FARMING phenylethylamine A member of a family of organic compounds that contains three primary functional groups: the phenyl (-C6H5) group, ethyl (-C2H5) group, and amino (-NH2) group plasmid A small, circular piece of DNA, found in bacteria and capable of autonomous reproduction polyprotein See SUPERPROTEIN rave drug See DESIGNER DRUG receptor molecule A molecule to which some other molecule, ion, or chemical entity binds recombinant DNA DNA that has been produced by joining genetic material from two different sources Also, the process by which this type of DNA is produced Also known as chimeric DNA resin bead A small spherical object, usually made of a polymer such as cross-linked polyethylene, used as the solid support in a solid-phase synthesis experiment restriction endonuclease See RESTRICTION ENZYME Glossary 167 restriction enzyme An enzyme that recognizes certain sequences of nitrogen bases and breaks the bonds at some point within that sequence Also known as a restriction endonuclease scavenger resin A polymer that has been especially designed to react with excess reactant, by-products, or other species present in a reaction that must be removed in order to obtain a pure product schedule (drug) A category into which the federal government classifies certain drugs, based on their potential medical use and their possibility for illicit use solid-phase synthesis One of the most common methods of combinatorial chemistry, by which large numbers of compounds are produced simultaneously while anchored to some kind of solid support, such as a resin bead solution-phase synthesis A common form of combinatorial chemistry in which large numbers of compounds are produced simultaneously in reactions carried out in a solution-phase Also called parallel synthesis or multiple parallel synthesis species In chemistry, a general term used to describe any type of particle, such as atoms, molecules, ions, or fragments of these particles split and mix system (of solid-phase synthesis) A method of making large numbers of compounds simultaneously on solid supports in which the components are first separated from each other, then split into separate parts, then recombined, and so on structure-activity relationships A field of drug synthesis in which the physical shape of a receptor site, enzyme substrate, or other biological structure is used for the design of a new drug substance P A substance thought to be responsible for the transmission of pain messages in the body substituent An atom or group of atoms inserted into a molecule in place of some other atom (often hydrogen) or group of atoms substrate The portion of a molecule, cell, organism, or some other structure on which an enzyme operates superprotein A long-chain molecule that contains within itself subunits, each of which has some important biological function Also known as a polyprotein synaptic gap The space between two neurons 168 CHEMISTRY OF DRUGS temporary unrousable unconsciousness A type of coma that can be life-threatening transgenic organism An organism that contains DNA from some second organism that has been transplanted into it triad A set of three nitrogen bases in an RNA or DNA molecule that codes for a specific amino acid Also called a codon vector (biological) An agent, such as a plasmid or a virus, used to transplant a gene into a host organism ◆ FURTHER READING PRINT Abraham, Donald J Burger’s Medicinal Chemistry and Drug Discovery 6th ed vol New York: Wiley-Interscience, 2003 Aldridge, Susan Magic Molecules: How Drugs Work Cambridge: Cambridge University Press, 1998 Bannworth, Willi, and Eduard Felder, eds Combinatorial Chemistry: A Practical Approach Weinheim, Germany: Wiley-VCH, 2000 Buchanan, J F “ ‘Designer Drugs.’ A Problem in Clinical Toxicology,” Medical Toxicology and Adverse Drug Experience (January/December 1988): 1–17 Cabri, Walter, and Romano De Fabio From Bench to Market: The Evolution of Chemical Synthesis New York: Oxford University Press, 2000 Dye, Christina Drugs and the Body: How Drugs Work Tempe, Ariz.: Do It Now Foundation, 1997 Also available online at http://www.doitnow org/pdfs/223.pdf Fletcher, Andrew J., et al., eds Principles and Practice of Pharmaceutical Medicine New York: John Wiley & Sons, 2002 Heinrich, M., and S Gibbons “Ethnopharmacology in Drug Discovery: An Analysis of Its Role and Potential Contribution,” Journal of Pharmacy and Pharmacology vol 53, no 4, April 2001: 425–432 Henderson, Gary “Designer Drugs: The New Synthetic Drugs of Abuse,” in A Church and F Sapienza, Proceedings of Controlled Substance Analog Leadership Conference Washington, D.C.: U.S Department of Justice, Drug Enforcement Administration, Office of Diversion Control, 1986 Hilisch, A., and R Hilgenfeld, eds Modern Methods of Drug Discovery Basel: Birkhäuser Verlag, 2003 Jenkins, Philip Synthetic Panics: The Symbolic Politics of Designer Drugs New York: New York University Press, 1999 Jollès, P., ed New Approaches to Drug Development Basel: Birkhäuser Verlag, 2000 169 170 CHEMISTRY OF DRUGS Jungmittag, Andre, Guido Reger, and Thomas Reiss, eds Changing Innovation in the Pharmaceutical Industry: Globalization and New Ways of Drug Development Berlin: Springer, 2000 Landers, Peter “Drug Industry’s Big Push into Technology Falls Short,” Wall Street Journal, February 24, 2004 Also available online at http:// www.mindfully.org/GE/2004/Drug-Industry-Falls-Short24feb04.htm Makiryannis, Alexandros, and Diane Biegel Drug Discovery Strategies and Methods New York: Marcel Dekker, 2004 Maulik, Sunil, and Salil D Patel Molecular Biotechnology: Therapeutic Applications and Strategies New York: Wiley-Liss, 1997 McGavock, Hugh How Drugs Work: Basic Pharmacology for Healthcare Professionals Abingdon, U.K.: Radcliffe Medical Press, 2002 Ng, Rick Drugs: From Discovery to Approval Hoboken, N.J.: Wiley-Liss, 2004 Oxender, Dale L., and Leonard E Post Novel Therapeutics from Modern Biotechnology: From Laboratory to Human Testing Berlin: Springer, 1999 Rintoul, Scott, and Christy MacKilliean Designer Drugs and Raves 2nd ed Vancouver, B.C.: National Crime Prevention Council, 2001 Also available online at http://www.rcmp-fairmont.org/da/docs/rave.pdf Rouhi, A Maureen “Rediscovering Natural Products.” Chemical & Engineering News vol 81, no 41, October 13, 2003, pp 77–78+ Also available online at http://pubs.acs.org/cen/coverstory/8141/ 8141pharmaceuticals.html Scientific Section (Laboratory), Policy Development and Analysis Branch, Division for Operations and Analysis Terminology and Information on Drugs 2nd ed Vienna: United Nations, Office on Drugs and Crime, 1998 Seneci, Pierfausto Solid Phase Synthesis and Combinatorial Technologies New York: John Wiley & Sons, 2000 Shulgin, Alexander T., and D E Nichols “Characterization of three new psychotomimetics,” in R C Stillman and R E Willette, The Pharmacology of Hallucinogens, New York: Pergamon, 1978 ———, and Ann Shulgin PiHKAL: A Chemical Love Story Berkeley, Calif.: Transform Press, 1991 ——— TiHKAL: The Continuation Berkeley, Calif.: Transform Press, 1997 Terrett, Nicholas K Combinatorial Chemistry Oxford: Oxford University Press, 1998 Thiericke, R., and S Grabley, eds Drug Discovery from Nature Berlin: Springer, 1999 Thomas, Gareth Medicinal Chemistry: An Introduction Chichester, U.K.: John Wiley & Sons, 2000 Torrence, Paul F., ed Biomedical Chemistry: Applying Chemical Principles to the Understanding and Treatment of Disease New York: John Wiley & Sons, 2000 Torssell, Kurt B Natural Product Chemistry: A Mechanistic and Biosynthetic Approach to Secondary Metabolism Chichester, U.K.: John Wiley & Sons, 1983 Tringali, Corrado, ed Bioactive Compounds from Natural Sources: Isolation, Characterisation and Biological Properties London: Taylor & Francis, 2001 Further Reading 171 INTERNET a1b2c3.com “Recreational Drugs Information.” a1b2c3.com Available online URL: http://www.a1b2c3.com/drugs/ Downloaded on August 17, 2005 ARBEC “Biotechnology and Natural Products,” ASEAN Review of Biodiversity and Environmental Conservation Available online URL: http://www.arbec.com.my/biotech.htm Posted on March 14, 2001 Batchelder, Tim “Natural Products from the Sea: Ethnopharmacology, Nutrition and Conservation,” FindArticles.com Available online URL: http://articles.findarticles.com/p/articles/mi_m0ISW/is_2001_Feb/ ai_70777319 Originally in Townsend Letter for Doctors and Patients 211 (February 2001): 136–141 BBC Science & Nature “Plant Pharming,” BBC Available online URL: http://www.bbc.co.uk/science/genes/gene_safari/pharm/plant_ p.shtml Downloaded on August 16, 2005 Betsch, David F “Pharmaceutical Production from Transgenic Animals,” Biotechnology Information Series, Iowa State University Extension and Office of Biotechnology Available online URL: http://www.biotech iastate.edu/biotech_info_series/bio10.html Updated on June 28, 2001 Bevan, David R “QSAR and Drug Design,” Network Science, Department of Biochemistry and Aerobic Microbiology, Virginia Polytechnic Institute and State University Available online URL: http://www netsci.org/Science/Compchem/feature12.html Posted January 1996 Center for Emerging Issues “Animal Pharming: The Industrialization of Transgenic Animals,” Animal and Plant Health Inspection Service Available online URL: http://www.aphis.usda.gov/vs/ceah/cei/ animal_pharming.htm Posted December 1999 Center for Science in the Public Interest “The Future of Pharming: Can It Be Done Safely?” Transcript of a CSPI conference on emerging technologies, held December 17, 2002 Available online URL: http://www cspinet.org/new/200212301.html Posted on December 30, 2002 Cooper, Donald A “Future Synthetic Drugs of Abuse,” Designer-Drugs com Available online URL: http://designer-drugs.com/synth/index html Downloaded on August 16, 2005 Cunningham, A B “Ethics, Biodiversity, and New Natural Product Development,” People and Plants Online Available online URL: http:// peopleandplants.org/web-content/web-content%201/dp/dp2/index html Downloaded on September 5, 2006 DEA “DEA Resources for Law Enforcement Officers,” U.S Drug Enforcement Administration Available online URL: http://www.usdoj gov/dea/pubs/ Downloaded on August 16, 2005 Erowid “Psychoactive Chemicals,” Erowid Available online URL: http:// www.erowid.org/chemicals Updated on August 16, 2005 Gerritz, Samuel W “Whither Solid Phase Synthesis?” Current Drug Discovery Available online URL: http://www.currentdrugdiscovery com/pdf/2002/6/gerritz.pdf Posted June 2002 172 CHEMISTRY OF DRUGS Gillespie, David “Pharming for Farmaceuticals,” Genetic Science Learning Center at the University of Utah Available online http://gslc.genetics utah.edu/features/pharming/ Downloaded on August 16, 2005 The Menarini Group “Birth of a Drug,” The Menarini Group Available online URL: http://www.menarini.com/english/ricerca_sviluppo/ farmaco.htm Downloaded on August 16, 2005 Mitscher, Lester A., and Apurba Dutta “Combinatorial Chemistry and Multiple Parallel Synthesis,” John Wiley & Sons, Inc Available online URL: http://media.wiley.com/product_data/excerpt/82/04713702/ 0471370282.pdf Originally published in Burger’s Medicinal Chemistry and Drug Discovery, edited by Donald J Abraham Vol 2, Drug Discovery and Development Hoboken, N.J.: Wiley, 2003 National Institute on Drug Abuse “Ecstasy: What We Know and Don’t Know About MDMA: A Scientific Review,” National Institute on Drug Abuse Available online URL: http://www.nida.nih.gov/PDF/ MDMAConf.pdf Updated on February 2, 2005 PBS Online “Animations: How Drugs Work,” PBS Online: Close to Home Available online URL: http://www.pbs.org/wnet/closetohome/ science/html/animations.html Downloaded on September 5, 2006 Pew Initiative on Food and Biotechnology, et al “Pharming the Field,” proceedings of a workshop held July 17–18, 2002 Available online URL: http://pewagbiotech.org/events/0717/ConferenceReport.pdf Posted on February 28, 2003 Shulgin, Alexander, “Utopian Pharmacology,” Erowid Available online URL: http://www.mdma.net/index.html Downloaded on September 5, 2006 Sneden, Albert T “Natural Products as Medicinally Useful Agents,” Leaf Squeezers Web Available online URL: http://www.people.vcu.edu/ ~asneden/MEDC%20310%20Intro.htm Updated June 21, 2005 Walters, D Eric “Where Do New Drugs Come From?” Department of Biochemistry & Molecular Biology, Rosalind Franklin University Available online URL: http://www.finchcms.edu/cms/biochem/ walters/walters_lect/walters_lect.html Downloaded on August 17, 2005 ◆ Italic page numbers indicate illustrations 1-(1-(2-thienyl- cyclohexyl)-piperdine 107 1-(1-phenyl- cyclohexyl)-pyrrolidine 1071-[2-phenylethyl]4-acetyloxypiperdine 105 1-methyl-4-phenyl1,2,5,6-tetrahydropyridine 105 1-methyl-4-phenyl4-piper-idinecarboxylic acid ethyl ester See meperidine 1-methyl-4-phenyl4-propionoxypiperidine 105 1-phenylcyclo-hexylamine 107 1-phenylcyclo-hexylpiperidine See phencyclidine 1-piperidinocyclohexanecarboni-trile 107 1,4-butanediol 110 2-(methylamino)2-(2-chlorophenyl)cyclohexanone See ketamine INDEX 2,5-dimethoxyamphetamine 99 3,4-methylenedioxy-Nethylamphet-maine See MDEA 3,4-methylenedioxyamphetmaine See MDA 3,4-methylenedioxymethampheta-mine See MDMA 3,4,5-trimethoxyamphetamine 99 4-bromo-2,5-dimethoxyampheta-mine 99 4-methoxyam-phetamine 99 4-methyl-2,5-dimethoxyam-phetamine 99 5-methoxy-3, 4-methylenedioxyamphetamine 99 A acetaminophen 130–131 acquired immunodeficiency syndrome See AIDS adenine 55, 55 173 ADHD See attention deficit hyperactivity disorder ADR See adverse drug reactions adrenaline See epinephrine adverse drug reactions (ADRs) 88 Aequora victoria 32 AIDS 7–8, 17, 38, 120–122 alcohol 10, 84 Alfenta 93 alfentanyl 93 alpha helix 56, 57 alpha interferon 64, 71 alpha-1-antitrypsin 73, 75 alpha-lactalbumin 75 alprazolam 110 alterplase 71 amphetamine 94, 97 amphetamines 14 analogs See specific drugs androstenedione 52 angel dust See phencyclidine annual wormwood See qing hoa 174 CHEMISTRY OF DRUGS antibiotics discovery 29 mechanism of action 29–30 Anti-Drug Abuse Act of 1988 91 antiviral drugs Arber, Werner 64–65 aresunate 26, 28 aristolochic acid 50 arteether 26, 28 artemether 26, 28 Artemisia annua 25 artemisine 26–27, 28 arylethanamines 94 arylethylamines 94 aspart 69 aspirin 2, 48, 115 Ativan 110 attention deficit hyperactivity disorder (ADHD) 95 B bacitracin 29 Bartels, John R., Jr 90 B-cell lymphoma 78 Bechler, Steve 51 Benzedrine 95 Berg, Paul 58–59 Bergmann, W 32 beta interferon 71 bhang 23 biodiversity 40 biological activity 25 biotechnology 54 bipolar disorder 10 black cohosh 46 blood clotting factor 65 bradykinesia 13 Brotzu, Giuseppe 29 Brown, Alexander Crum 133–134 Brown, William 22 bryostatin-1 33 Buchanan, J F 89 Bunnell, S 98 Bureau of Drug Abuse Control 91 Bureau of Narcotics 91 Bureau of Narcotics and Dangerous Drugs 91 Burke, D C 32 Burkholder, Paul 29 C camptothecin 36 cancer 78 Caventou, JosephBienaimé 24 Centralgin 104 Centrax 110 cephalosporins 29 chamomile 48, 49 chemotherapy 86 chimeric DNA 54 China White See Fentanyl, analogs; meperidine, analogs chloramphenicol 29 chlordiazepoxide 110 chlortetracycline 29 cholera 78 Chondrodendron tomentosum 23 chondroitin 41 circles See Rohypnol clorazepate 110 club drugs See designer drugs coagulation factor IX 71 cocaine 10, 14, 126, 126 codeine 124 codon See triad coenzyme Q10 46 collagen I 75 collagen II 75 colon cancer 37 combinatorial chemistry x, 134–158 applications 156–158 general principles 134–136, 136 combretastatin A4 38 comfrey 50 Controlled Substances Act of 1970 3–7, 91 Convention on Biological Diversity 54 Convention on International Trade in Endangered Species 40 Cordus, Valerius 22 curare 12, 23 Curran, Dennis 152 Cytosar-U 33 cytosine 55, 55 D Dalmane 110 date rape 111 Datril xi DEA See U.S Drug Enforcement Agency deconvolution 146–148 Deep Vent DNA polymerase 32 Demerol 104 dental caries 78 deoxyribonucleic acid See DNA deoxyribose 54–55, 55 designer drugs 83–113 definition 85–88 illegal 89–113 Dexedrine 95 diabetes 53–54 diazepam 110 Dietary Supplement Health and Education Act Index (DSHEA) of 1994 43–45 dietary supplements 41–46, 46 disease prevention 7–10 disease-directed designer drugs (DDDD) 87–88 Dispensatorium (Cordus) 22 dissociative anesthesia 106 DMA See 2,5-dimethoxy-amphetamine DNA 54–56 three-dimensional structure 56, 57 DOB See 4-bromo2,5-dimethoxy-amphetamine Dohme, A R L 127 Dolantin 104 dolastatin 10 33 Dolly (cloned sheep) 73 DOM See 4-methyl2,5-dimethoxy-amphetamine Domagk, Gerhard 116 Dooley, C T 151 dopamine 13–14, 94, 103, 126 Doral 110 Drug Abuse Warning Network (DAWN) 99 drug analogs 116–117 drug development x, 115–117 future prospects 17–19, 159–162 rational drug design 117–158 serendipity 116 trial-and-error methods 115–116 drug deals drug interactions 48–49 drugs early history 1–3 from marine organisms 30–33 from micro-organisms 28–30 from plant products 33–38 from recom-binant DNA 64–77 hallucenogenic 22–23 health claims 41–46 mind-altering 10–17 recreational 89–92, 161 religious uses 89 types 3–7 D-tubocurarine 23 Duggar, Benjamin Minge 29 E echinacea 40, 41, 49 Ecstasy 85, 99 ecteinascidin 743 33 Edeleanu, Lazar 94 Ehrlich, John 29, 116, 123 Eighteenth Amendment 84 Eisleb, Otto 104 Elliott, Thomas R 15 endorphins 14, 16–17, 19 enkephalins 14, 16–17, 19 enterotoxigenic E coli 78 enzyme action 119– 120, 119 lock-and-key model 119–120 175 ephedra 50–52 epinephrine 94 Epogen 80 Eprex 80 erythropoietin 65, 75 estazolam 110 ethnobotany 39 ethnopharmacology 115–116 etoposide 34 Excedrin xi F factor VIII 75 factor IX 75 FDA See U.S Food and Drug Administration Feeney, R J 32 Fentanyl 93 analogs 92–94 physiological effects 93–94 use statistics 94 fibrinogen 75 Fischer, Emil 119 fish oil 48 Fleming, Sir Alexander 28, 116 flunitrazepam See Rohypnol fluorous synthesis 152–153 flurazepam 110 folic acid 51 foot-and-mouth disease 78 Formulaid 32 Fortovase 122 Fraser, T R 134 G Gallo, Robert gamma butyrolactone See GBL gamma hydroxybutyric acid See GHB 176 CHEMISTRY OF DRUGS gamma hydroxyvalerate See GHV gamma-oh! See GHB gamma valerolactone See GVL garlic 46 GBL 110 gene 60 genetic code 56–60 genetic engineering 54 Genotropin 70 Georgia home boy See GHB Geysen, H Mario 145 GFP See green fluorescent protein GHB 108–111 health effects 109–110 GHV 110 ginger 48, 49 gingko 41, 48 ginseng 40, 41, 48 Gleevic 86 Glivec 86 glucosamine 41, 48 glutamic acid decarboxylase 75 goldenseal 40, 48, 49 goop See GHB Gotlieb, David 29 granulocyte-colony stimulating factor (G-CSF) 65 granulocyte-macrophage colonystimulating factor (GMCSF) 65 green fluorescent protein (GFP) 32 green tea 46 grievous bodily harm See GHB guanine 55, 55 Gund, Peter 123 GVL 110 H halazepam 110 Halcion 110 halichondrin B 33 hallucinogens 89 halomon 33 Hammett, Louis Planck 132–133, 134 Hammett constant 134 Hammett equation 132, 133, 134 hashish 92 hawthorne 42 Henderson, Gary 89 hepatitis B vaccine 65, 71 herbal medicines See natural products heroin 10, 14, 124 herpes simplex 78 HIV 7–8, 17, 61, 120–122 HOE 901 69 hog See phencyclidine homoharringtonine 38 Houghten, Richard 144, 151 Huang Ti Nei Ching Su Wen 21 Humalog 68 human cytomegalovirus 78 Human Genome Project 87 human growth hormone 65, 70, 71, 75 human immunodeficiency virus See HIV human lactoferrin deficiency 78 human lysozyme deficiency 78 human protein C 75 Humatrope 70 Huntington’s chorea 10 hypopituitary dwarfism 78 I imatinib 86 imiglucerase 71 indexed libraries 150 ingenol 38 insulin 64, 65–68, 68, 71 analogs 68–70 molecular structure 6c68, 67 insulin detemir 69 Invirase 122 irinotecan 34 isoflavone 51 J Jacobsohn, W 96 K kava 42, 48, 50 ketamine 107–108 health effects 108 Koch, Robert Kötz, A 106 L Laborit, Henri 109 lactoferrin 75 Landers, Peter 157 lead compounds 115–116 Lechevalier, Hubert 29 Librium 110 ligase 63 linkers 142–144, 143 Lipitor 114, 115 liquid E See GHB liquid X See GHB Liquiprin xi lispro 68 Index Lititz Pharmacopoeia (Brown) 22 Loewi, Otto, 15 lorzepam 110 LSD 98 L-tryptophan 50 Luria, Salvador 64 lysergic acid diethylamide See LSD M ma huang See ephedra malaria 24 Mannish, G 96 MDA 96I97 MDEA 96 MDMA 96–104, 97 health effects 102–103, 102 melanoma 33 Meleney, Frank 29 Meperidin 104 meperidine 104 analogs 104–106 Merck, Emanuel 24 Merkel, P J 106 Merrifield, Bruce 136, 138–139 mescaline 94 methamphetamine 95–96, 97 Methedrine 95 Mexican valium See Rohypnol(r) Mifeprex 130 mifepristone 130 milk thistle 46 Misuse of Drugs Act 99 MMDA See 5-methoxy-3,4-methylenedio-xyamphe-tamine Mogil, Jeffrey, 88 molecular farming 76–77 Molecules of Emotion: The Science Behind Mind–Body Medicine (Pert) 19 monoclonal antibody 79 Montagnier, Luc morphine 14, 24, 124 MPPP See 1-methyl4-phenyl-4-propionoxypiperidine MPTP See 1-methyl-4phenyl-1,2,5,6-tetrahydro-pyridine multipin system 145–146, 145 multiple parallel synthesis See solutionphase synthesis Murex brandaris 30 N National Cancer Institute (NCI) 34–35, 38 National Institute of Drug Abuse 102–103, 111 natural products (as drugs) as dietary supplements 41–46 history 21–23 modern developments 23–27 research 40–41 risks 49–52 safety 47–52 Navia, Manuel A 121 nelfinavir 122 neomycin 29 nerve transmission 10–17, 11 N-ethyl-1-phenyl-cyclohexylamine 107 neurotransmitters 10–17, 12, 13 new heroin See meperidine, analogs 177 Newman, David 156–157 new molecular entities (NME) 115 niacin 51 nicotine 14 nitrogen bases 55, 55 Nixon, Richard M 90 NME See new molecular entities Noble, Clark 34 Noble, Robert Laing 34 nomenclature, drug xi non-Hodgkin’s lymphoma 33 Norditropin 70 Norwalk virus 78 NovoLog 69 NovoSol Basal 69 nucleoside 55, 56 nucleotide 55, 56 Nutropin 70 O Office of Drug Abuse Law Enforcement (ODALE) 90 Ogata, Akira 95 oligonucleotide 62 opiate receptors 14, 16–17 opiates 124, 125 opium 14 optical isomerism 95 orphan drugs 33 orthogonal libraries See indexed libraries ovarian cancer 33, 37 oxazepam 110 ozone See phencyclidine P PABA 8–10 paciltaxel 35–37 pain, mechanism of 14, 16–17, 16 178 CHEMISTRY OF DRUGS para-amino benzoic acid See PABA Paracetamol xi parallel synthesis See solution-phase synthesis Parkinson’s disease 13–14, 105–106 Pasteur, Louis patient-directed designer drugs (PDDD) 87–88 Paxipam 110 PCC See 1-piper-idinocyclohexane-carbonitrile PCE See N-ethyl-1phenyl-cyclohexylamine PCP See phencyclidine PCPy See 1-(1-phenylcyclo-hexyl)-pyrrolidine Pelletier, PierreJoseph 24 penicillin 116 discovery 28–29 PEPAP See 1[2-phenylethyl]4-acetyloxypiperdine peptide synthesis (Merrifield method) 137–143, 137 Pert, Candace Beebe 18–19 Pethidine 104 pharmacogenomics 85 pharmacophore 123–126, 124 modifications 127–131 size and shape 127–130 new substituents 130–131 pharming 72–82, 160 benefits 74 defined 72 procedure 74–77 products 75 pros and cons 77–82 risks 73 phencyclidine 106 analogs 106–108 health effects 107–108 phenoxodiol 38 phenylethylamine 94 analogs 94–95 Philadelphia chromosome-positive chronic myeloid leukemia 86–87 phosphate 55, 55 PHP See 1(1-phenylcyclohexyl)-pyrrolidine PiHKAL (Phenylethylamines I Have Known and Loved: A Chemical Love Story) (Shulgin and Shulgin) 101 Plantibodies 76 plasmid 63 PMA See 4-methoxyamphetamine poison dart frogs 23 prazepam 110 prednisone 130 Procrit 80 ProSom 110 protease inhibitors 121–122, 122 proteases 121 protein synthesis 56–60 Protropin(r) 70 pseudopterosin 30–31, 31 pumiliotoxin 23 Q qing hoa 25 QSAR See quantiative structure-activity relationships quantitative structureactivity relationships (QSAR) 131–134, 161 quazepam 110 quinghaosu See artemisinine quinine 24, 26, 27 analogs 25 synthesis 25, 26 R R-2 See Rohypnol rabbit hemorrhagic disease virus 78 rabies 78 rational drug design 160–161 rave drugs See designer drugs receptor molecules 10, 14 recombinant DNA x, 160 drug products 64–77 principles 54–61 process 61–64 Reefer Madness (motion picture) 84 Resilience 30 Restoril 110 restriction endonuclease See restriction enzyme restriction enzyme 62, 63 rib See Rohypnol ribonucleic acid See RNA RNA 56 Robinson, Arthur B 139 Index Robinson, Sir Robert 24 rocket fuel See phencyclidine Rohypnol 108–111 roofies See Rohypnol ropies See Rohypnol royal purple See Tyrian purple RU-486 130 Ruff, Michael 19 S St John’s wort 42, 46, 48 Saizen 70 salicylic acid 115 saquinavir 122 SAR See structure-activity relationships Sargent, T 98 saw palmetto 42 scavenger resins 153–155, 154, 155 Schaumann, Otto 104 schedules, drug 3–7, 92 schizophrenia 126 Serax 110 Sernyl 106 Serostim 70 serotonin 103 Sertürner, Friedrich Wilhelm 24 Shiva 23 Shulgin, Alexander “Sasha” 98, 100–101 Shulgin, Ann 101 solid-phase synthesis 136–148 solution-phase synthesis 148–156 split and mix system 140–142, 141 ST1571 86 StarLink 80 Staudinger, Hermann 133 STP See 4-methyl2,5-dimethoxy-amphetamine streptokinase 65 streptomycin 29 structure-activity relationships (SAR) x, 118–158, 161 Sublimaze 93 substance P 14, 16 Sufenta 93 sufentanyl 93 sulfacetamide 91 sulfa drugs 90–91 mode of action 8–9, sulfamethoxazole 91 sulfanilamide 90–91, 116 analogs 117–118 sulfasalazine 91 sulfisoxazole 91 superproteins 121 superweed See phencyclidine sweet annie See qing hoa sweet wormwood See qing hoa synaptic gap 10, 12 synthetic Demerol See meperidine, analogs synthetic heroin See Fentanyl, analogs T Taxol xi, 33, 34, 35, 36, 39 TCP See 1-(1-(2-thienyl- cyclohexyl)-piperdine temazepam 110 temporary unrousable unconsciousness 110 Tempro xi teniposide 34 179 Tev-Tropin 70 THC See phencyclidine thunder god vine 46 thymine 55, 55 TiHKAL (Tryptamines I Have Known and Loved: The Chemistry Continues) (Shulgin and Shulgin) 101 tissue plasminogen activator 75 TMA See 3,4, 5-trimethoxyamphetamine topotecan 34 TPCP See 1-(1-(2thienyl- cyclohexyl)piperdine traditional medicine 20–23 transgenic animal 62, 74 transmissible gastroenteritis coronavirus 78 Tranxene 110 triad (DNA) 56 triazolam 110 Tylenol xi, 130 Tyrian purple 30 tyrosine 94 U “uppers” 96 U.S Central Intelligence Agency (CIA) 98 USDA See U.S Department of Agriculture U.S Department of Agriculture (USDA) 38 Natural Products Branch 38–39 180 CHEMISTRY OF DRUGS U.S Department of Health and Human Services 44, 99 U.S Drug Enforcement Administration (DEA) 84, 90–91, 100–101 U.S Food and Drug Administration (FDA) 44, 64, 70, 74, 91 V vaccine, edible 79 valerian 42, 43, 49 Valium 110 vector 63 Vent DNA polymerase 32 Vietnam War 25 vinblastine 34 Vinca rosea 34 vincristine 34 Viracept 122 vitamin E 48 von Eggers, William 25 White House Office of National Drug Control (ONDCP) 91 Woodward, Robert Burns 25, 26–27 Woolley, D W 138 World Health Organization 20 X Xanax 110 W wack See phencyclidine Waksman, Selman 29 Wall, Monroe 35, 36, 36–37, 38 Wani, M C 35, 36–37, 38 Y Yellow Emperor’s canon of internal medicine See Huang Ti Nei Ching Su Wen yohimbe bark 42 yohimbine 50 ... composition of foods vii viii CHEMISTRY OF DRUGS and drugs The set title The New Chemistry has been selected to emphasize the extensive review of recent research and advances in each of the fields of chemistry. .. areas of research not typically included in the beginning middle or high school curriculum in chemistry The six books in the set Chemistry of Drugs, Chemistry of New Materials, Forensic Chemistry, ... and the Rise of Modern Chemistry Robert Burns Woodward (1917–1979) Microorganisms as the Source of Drugs Marine Organisms as a Source of Drugs Plant Products as the Source of New Drugs Monroe